Abstract
The heat shock response (HSR) pathway is a highly conserved rescue mechanism, which protects the cells from harmful insults disturbing the cellular protein homeostasis via expression of chaperones. Furthermore, it was demonstrated to play crucial roles in various diseases like neurodegeneration and cancer. For neurodegenerative diseases, an overexpression of chaperones is a potential therapeutic approach to clear the cells from non-functional protein aggregates. Therefore, activators of the HSR pathway and its master regulator HSF1 are under close observation. There are numerous HSR activators published in the literature using different model systems, experimental designs, and readout assays. The aim of this work was to provide a quantitative comparison of a broad range of published activators using a newly developed HSF responsive dual-luciferase cell line. Contrary to natural target genes, which are regulated by multiple input pathways, the artificial reporter exclusively reacts to HSF activity. In addition, the results were compared to endogenous heat shock protein expression. As a result, great differences in the intensity of pathway activation were observed. In addition, a parallel viability assessment revealed high variability in the specificity of the drugs. Furthermore, the differences seen compared to published data indicate that some activators exhibit tissue-specific differences leading to interesting assumptions about the regulation of HSF1.
Highlights
When Ritossa first discovered the heat shock response (HSR) in 1962, a whole new research field was initiated [1]
In order to determine if the more sensitive response seen on Hsp72 protein level compared to the HEK293-based reporter cell lines is caused by an Heat Shock Factor 1 (HSF1) independent mechanism, or due to the sensitivity of the cell lines used, we looked at a WI38-based reporter cell line (Fig. 2d)
They can either be used to study the molecular mechanisms of the HSR in detail, or manipulate HSF1 activity as a potential therapeutic approach in various diseases, ranging from neurodegenerative (Alzheimer’s, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS)) to metabolic diseases
Summary
When Ritossa first discovered the heat shock response (HSR) in 1962, a whole new research field was initiated [1]. A vast amount of papers on this topic were published in the following years, until today. The heat shock response pathway has become more and more important, as a highly conserved cellular rescue mechanism after stressful insults and its correlation to thermal tolerance [2], and because it plays an important role in wide-ranged varieties of diseases in humans, for instance neurodegenerative diseases and cancer [3–9]. The HSR can be triggered by heat, but by various stressors like changes in pH or oxygen levels, heavy metals, Christoph Steurer and Sarah Kerschbaum contributed to this work These modifications were considered essential for the activation, Molecular Biotechnology (2022) 64:873–887 a more recent publication suggests only minor finetuning potential for the phosphorylation [19]
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